Acquired Resistance of ER-Positive Breast Cancer to Endocrine Treatment Confers an Adaptive Sensitivity to TRAIL through Posttranslational Downregulation of c-FLIPCitation formats

  • External authors:
  • Luke Piggott
  • Andreia Silva
  • Timothy Robinson
  • Michael Becker
  • Iduna Fichtner
  • Ladislav Andera
  • Philippa Young
  • Christine Morris
  • Peter Barrett-Lee
  • Fouad Alchami
  • Marco Piva
  • Maria dM Vivanco
  • Julia Gee
  • Richard Clarkson

Standard

Acquired Resistance of ER-Positive Breast Cancer to Endocrine Treatment Confers an Adaptive Sensitivity to TRAIL through Posttranslational Downregulation of c-FLIP. / Piggott, Luke; Silva, Andreia; Robinson, Timothy; Santiago-Gómez, Angelica; Simões, Bruno M; Becker, Michael; Fichtner, Iduna; Andera, Ladislav; Young, Philippa; Morris, Christine; Barrett-Lee, Peter; Alchami, Fouad; Piva, Marco; Vivanco, Maria dM; Clarke, Robert B; Gee, Julia; Clarkson, Richard.

In: Clinical Cancer Research, Vol. 24, No. 10, 15.05.2018, p. 2452-2463.

Research output: Contribution to journalArticlepeer-review

Harvard

Piggott, L, Silva, A, Robinson, T, Santiago-Gómez, A, Simões, BM, Becker, M, Fichtner, I, Andera, L, Young, P, Morris, C, Barrett-Lee, P, Alchami, F, Piva, M, Vivanco, MDM, Clarke, RB, Gee, J & Clarkson, R 2018, 'Acquired Resistance of ER-Positive Breast Cancer to Endocrine Treatment Confers an Adaptive Sensitivity to TRAIL through Posttranslational Downregulation of c-FLIP', Clinical Cancer Research, vol. 24, no. 10, pp. 2452-2463. https://doi.org/10.1158/1078-0432.CCR-17-1381

APA

Piggott, L., Silva, A., Robinson, T., Santiago-Gómez, A., Simões, B. M., Becker, M., Fichtner, I., Andera, L., Young, P., Morris, C., Barrett-Lee, P., Alchami, F., Piva, M., Vivanco, M. DM., Clarke, R. B., Gee, J., & Clarkson, R. (2018). Acquired Resistance of ER-Positive Breast Cancer to Endocrine Treatment Confers an Adaptive Sensitivity to TRAIL through Posttranslational Downregulation of c-FLIP. Clinical Cancer Research, 24(10), 2452-2463. https://doi.org/10.1158/1078-0432.CCR-17-1381

Vancouver

Author

Piggott, Luke ; Silva, Andreia ; Robinson, Timothy ; Santiago-Gómez, Angelica ; Simões, Bruno M ; Becker, Michael ; Fichtner, Iduna ; Andera, Ladislav ; Young, Philippa ; Morris, Christine ; Barrett-Lee, Peter ; Alchami, Fouad ; Piva, Marco ; Vivanco, Maria dM ; Clarke, Robert B ; Gee, Julia ; Clarkson, Richard. / Acquired Resistance of ER-Positive Breast Cancer to Endocrine Treatment Confers an Adaptive Sensitivity to TRAIL through Posttranslational Downregulation of c-FLIP. In: Clinical Cancer Research. 2018 ; Vol. 24, No. 10. pp. 2452-2463.

Bibtex

@article{a43987f735384bdfb69f733e2109e418,
title = "Acquired Resistance of ER-Positive Breast Cancer to Endocrine Treatment Confers an Adaptive Sensitivity to TRAIL through Posttranslational Downregulation of c-FLIP",
abstract = "Purpose: One third of ER-positive breast cancer patients who initially respond to endocrine therapy become resistant to treatment. Such treatment failure is associated with poor prognosis and remains an area of unmet clinical need. Here, we identify a specific posttranslational modification that occurs during endocrine resistance and which results in tumor susceptibility to the apoptosis-inducer TRAIL. This potentially offers a novel stratified approach to targeting endocrine-resistant breast cancer.Experimental Design: Cell line and primary-derived xenograft models of endocrine resistance were investigated for susceptibility to TRAIL. Tumor viability, cancer stem cell (CSC) viability (tumorspheres), tumor growth kinetics, and metastatic burden were assessed. Western blots for the TRAIL-pathway inhibitor, c-FLIP, and upstream regulators were performed. Results were confirmed in primary culture of 26 endocrine-resistant and endocrine-na{\"i}ve breast tumors.Results: Breast cancer cell lines with acquired resistance to tamoxifen (TAMR) or faslodex were more sensitive to TRAIL than their endocrine-sensitive controls. Moreover, TRAIL eliminated CSC-like activity in TAMR cells, resulting in prolonged remission of xenografts in vivo In primary culture, TRAIL significantly depleted CSCs in 85% endocrine-resistant, compared with 8% endocrine-na{\"i}ve, tumors, whereas systemic administration of TRAIL in endocrine-resistant patient-derived xenografts reduced tumor growth, CSC-like activity, and metastases. Acquired TRAIL sensitivity correlated with a reduction in intracellular levels of c-FLIP, and an increase in Jnk-mediated phosphorylation of E3-ligase, ITCH, which degrades c-FLIP.Conclusions: These results identify a novel mechanism of acquired vulnerability to an extrinsic cell death stimulus, in endocrine-resistant breast cancers, which has both therapeutic and prognostic potential. Clin Cancer Res; 24(10); 2452-63. {\textcopyright}2018 AACR.",
author = "Luke Piggott and Andreia Silva and Timothy Robinson and Angelica Santiago-G{\'o}mez and Sim{\~o}es, {Bruno M} and Michael Becker and Iduna Fichtner and Ladislav Andera and Philippa Young and Christine Morris and Peter Barrett-Lee and Fouad Alchami and Marco Piva and Vivanco, {Maria dM} and Clarke, {Robert B} and Julia Gee and Richard Clarkson",
note = "{\textcopyright}2018 American Association for Cancer Research.",
year = "2018",
month = may,
day = "15",
doi = "10.1158/1078-0432.CCR-17-1381",
language = "English",
volume = "24",
pages = "2452--2463",
journal = "Clinical cancer research : an official journal of the American Association for Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research",
number = "10",

}

RIS

TY - JOUR

T1 - Acquired Resistance of ER-Positive Breast Cancer to Endocrine Treatment Confers an Adaptive Sensitivity to TRAIL through Posttranslational Downregulation of c-FLIP

AU - Piggott, Luke

AU - Silva, Andreia

AU - Robinson, Timothy

AU - Santiago-Gómez, Angelica

AU - Simões, Bruno M

AU - Becker, Michael

AU - Fichtner, Iduna

AU - Andera, Ladislav

AU - Young, Philippa

AU - Morris, Christine

AU - Barrett-Lee, Peter

AU - Alchami, Fouad

AU - Piva, Marco

AU - Vivanco, Maria dM

AU - Clarke, Robert B

AU - Gee, Julia

AU - Clarkson, Richard

N1 - ©2018 American Association for Cancer Research.

PY - 2018/5/15

Y1 - 2018/5/15

N2 - Purpose: One third of ER-positive breast cancer patients who initially respond to endocrine therapy become resistant to treatment. Such treatment failure is associated with poor prognosis and remains an area of unmet clinical need. Here, we identify a specific posttranslational modification that occurs during endocrine resistance and which results in tumor susceptibility to the apoptosis-inducer TRAIL. This potentially offers a novel stratified approach to targeting endocrine-resistant breast cancer.Experimental Design: Cell line and primary-derived xenograft models of endocrine resistance were investigated for susceptibility to TRAIL. Tumor viability, cancer stem cell (CSC) viability (tumorspheres), tumor growth kinetics, and metastatic burden were assessed. Western blots for the TRAIL-pathway inhibitor, c-FLIP, and upstream regulators were performed. Results were confirmed in primary culture of 26 endocrine-resistant and endocrine-naïve breast tumors.Results: Breast cancer cell lines with acquired resistance to tamoxifen (TAMR) or faslodex were more sensitive to TRAIL than their endocrine-sensitive controls. Moreover, TRAIL eliminated CSC-like activity in TAMR cells, resulting in prolonged remission of xenografts in vivo In primary culture, TRAIL significantly depleted CSCs in 85% endocrine-resistant, compared with 8% endocrine-naïve, tumors, whereas systemic administration of TRAIL in endocrine-resistant patient-derived xenografts reduced tumor growth, CSC-like activity, and metastases. Acquired TRAIL sensitivity correlated with a reduction in intracellular levels of c-FLIP, and an increase in Jnk-mediated phosphorylation of E3-ligase, ITCH, which degrades c-FLIP.Conclusions: These results identify a novel mechanism of acquired vulnerability to an extrinsic cell death stimulus, in endocrine-resistant breast cancers, which has both therapeutic and prognostic potential. Clin Cancer Res; 24(10); 2452-63. ©2018 AACR.

AB - Purpose: One third of ER-positive breast cancer patients who initially respond to endocrine therapy become resistant to treatment. Such treatment failure is associated with poor prognosis and remains an area of unmet clinical need. Here, we identify a specific posttranslational modification that occurs during endocrine resistance and which results in tumor susceptibility to the apoptosis-inducer TRAIL. This potentially offers a novel stratified approach to targeting endocrine-resistant breast cancer.Experimental Design: Cell line and primary-derived xenograft models of endocrine resistance were investigated for susceptibility to TRAIL. Tumor viability, cancer stem cell (CSC) viability (tumorspheres), tumor growth kinetics, and metastatic burden were assessed. Western blots for the TRAIL-pathway inhibitor, c-FLIP, and upstream regulators were performed. Results were confirmed in primary culture of 26 endocrine-resistant and endocrine-naïve breast tumors.Results: Breast cancer cell lines with acquired resistance to tamoxifen (TAMR) or faslodex were more sensitive to TRAIL than their endocrine-sensitive controls. Moreover, TRAIL eliminated CSC-like activity in TAMR cells, resulting in prolonged remission of xenografts in vivo In primary culture, TRAIL significantly depleted CSCs in 85% endocrine-resistant, compared with 8% endocrine-naïve, tumors, whereas systemic administration of TRAIL in endocrine-resistant patient-derived xenografts reduced tumor growth, CSC-like activity, and metastases. Acquired TRAIL sensitivity correlated with a reduction in intracellular levels of c-FLIP, and an increase in Jnk-mediated phosphorylation of E3-ligase, ITCH, which degrades c-FLIP.Conclusions: These results identify a novel mechanism of acquired vulnerability to an extrinsic cell death stimulus, in endocrine-resistant breast cancers, which has both therapeutic and prognostic potential. Clin Cancer Res; 24(10); 2452-63. ©2018 AACR.

U2 - 10.1158/1078-0432.CCR-17-1381

DO - 10.1158/1078-0432.CCR-17-1381

M3 - Article

C2 - 29363524

VL - 24

SP - 2452

EP - 2463

JO - Clinical cancer research : an official journal of the American Association for Cancer Research

JF - Clinical cancer research : an official journal of the American Association for Cancer Research

SN - 1078-0432

IS - 10

ER -